Alzheimer's disease (AD), the most frequent cause of dementia, is characterized by accumulation of amyloid plaques and formation of neurofibrillary tangles. Treatment of AD is a challenge because this devastating disease often coexists with other brain lesions caused by comorbidities, including obesity, diabetes, hypertension and cardiovascular diseases. Metabolic syndrome (MetS) is the early stage of these comorbidities and it is prevalent among veteran population. MetS in mid-life could interact with the asymptomatic cellular phase of AD and accelerate the disease progression. The role of comorbidities needs to be examined early because the comorbid population may take diverse paths in terms of disease management and the type of medications used. Therefore, epidemiological studies can sometime yield mixed findings in terms of their susceptibility to dementia. Studies of early interactions between MetS and AD, using comorbid models of AD, can identify converging pathways. In MetS, mitochondrial proteins are hyperacetylated, leading to their decreased function. This protein modification is reversed by the deacetylase enzyme, known as SIRT3, the focus of this study. SIRT3 downregulation is a critical component of MetS because (i) global knockout of Sirt3 in mice leads to acceleration of MetS, (ii) reduced human SIRT3 activity, caused by a single point mutation (V208I), is associated with MetS and (iii) chronic consumption of excessive calories, a cause of MetS, decreases SIRT3 levels and activity. While SIRT3 research has generally remained in the domain of peripheral tissues, its function in brain mitochondrial metabolism is beginning to emerge. We recently made the critical observations of hyperacetylation/downregulation of mitochondrial proteins, impaired mitochondrial respiration, and markers of neuroinflammation with the brain samples of Sirt3-/- mice. Therefore, we crossed these mice with Alzheimer's transgenic (APP/PS1) mice to generate APP/PS1/Sirt3-/- mice, as a comorbid AD model with MetS. Exacerbation of insulin resistance, amyloid pathology, neuroinflammation, microglial dysregulation and differential gene expression patterns (RNA-seq analysis) in the brain were observed in these mice. Our preliminary studies suggested that SIRT3 deficiency in MetS may cause metabolic dysregulation and neuroinflammation in midlife and accelerates cognitive decline in individuals susceptible for AD. The overall objective of this study is to dissect the causal mechanisms by examining the roles of SIRT3 deficiency in neurons, astrocytes and microglia of comorboid AD mouse brain. We hypothesize that ?SIRT3 deficiency and amyloid pathology interact through converging pathways of metabolic dysregulation and neuroinflammation in comorbid AD?. This hypothesis will be tested with the following Specific Aims: Aim 1. To determine the effects of SIRT3 deficiency on brain mitochondrial metabolism, insulin resistance and cognitive decline in APP/PS1/Sirt3-/- mice, a comorbid AD model Aim 2. To determine the effects of SIRT3 deficiency in different brain cell types on gene expression patterns and markers of metabolic stress in comorbid AD Aim 3. To determine the role of microglial dysregulation as a key component of SIRT3 deficiency- induced neuroinflammation Findings of this study will identify specific mechanisms by which MetS accelerates AD pathogenesis and place mitochondrial protein hyperacetylation upstream of neuroinflammation. Therapeutic targeting of SIRT3 in AD with coexisting pathologies has the potential to produce beneficial effects when combined with treatments that reduce Alzheimer's pathologies.